Description of the Related Art
Aneurysm, the enlargement of a blood vessel at a specific location—at times to the point where rupture of the blood vessel is imminent—has been treated in the past by surgical intervention techniques, where the affected portion of the blood vessel is removed or bypassed so that the vessel lumen is replaced by a synthetic graft. This treatment regimen is highly invasive, typically requiring a multiple day post-operative hospital stay, as well as several months of recuperative time.
Basically, aortic aneurysms are classified according to where they are located along the aorta. A thoracic aortic aneurysm is located along the segment of the aorta that passes through the chest, and an abdominal aortic aneurysm is located along the segment of the aorta that travels through the abdomen. In addition to the aorta, any other large blood vessel in the body may produce aneurysms, including those that provide blood to the lower extremities, heart or brain.
Prophylactic methods for preventing the formation of aneurysms tend to rely on reducing blood pressure in an effort to reduce mechanical stress on the blood vessels. These methods involve drugs that can have undesirable side effects, e.g., kidney or liver damage, especially over long-term use.
Typically, surgical intervention for aneurysm repair is not indicated until the blood vessel diameter at the aneurysmal site expands to 200 to 300% of its normal diameter. Below this threshold, the normal course of treatment has been to monitor the site, and if the diameter of the blood vessel wall at the aneurysmal site continues to expand beyond an undesirable threshold diameter, intervene surgically. Through numerous studies performed during the past decade, many of which were summarized by Thompson et al. in Curr. Probl. Surg., 39, 93 (2002), the basic knowledge of aneurysm disease has increased significantly. Given the fact that several pharmacological strategies, e.g., cyclooxygenase-2 (COX-2) inhibitors, tissue inhibitors of matrix metalloproteinases (MMP), and anti-inflammatories can reduce the severity and/or progression of an aneurysm in animal models, these approaches may also be able to limit the rate of aneurysm growth in humans.
Based on the current knowledge of the causes of aneurysms, MMP inhibition has been proposed as a potential therapeutic approach to treatment. Typical treatment requires the use of systemic MMP inhibitors, either orally, intra-muscularly or intravenously introduced, in a dosage sufficient to ensure that the quantity of agent reaching the aneurysm is sufficient to affect level of the elastin-attacking protein. For example, doxycycline could inhibit aneurysm growth in humans (see J. Vasc. Surg., 31, 325 (2000)); however, the side effects of doxycycline, including the likelihood of the patient developing doxycycline resistant bacteria as a result of long term doxycycline treatment, dictate that doxycycline treatment in high doses may be only a short term solution to the problem of aneurysm growth. Other approaches to treat aneurysms are the use of anti-inflammatory agents, including COX-2 inhibitors (see Circulation, 100, 48 (1999)), angiotensin-converting enzyme (ACE) inhibitors (see J. Vasc. Surg., 33, 1057 (2001)), nitric oxide synthase (NOS) inhibitors (see Ann. Vasc. Surg., 16, 65 (2002)), and antioxidants.
In view of the above considerations, it is clear that the present methods to treat aneurysms have limitations. Moreover, there is no practical pharmacological method available to prevent the aneurysm formation, without having to worry about the side effects of the drugs used, though U.S. Pat. No. 5,834,449 employs the use of a tetracycline compound having no antimicrobial activity which could limit drug associated side effects.
Thus, there exists a need to treat an aneurysmal site with therapeutic agents so as to reduce the severity and/or the progression of the aneurysm and the risk of aneurysm rupture, tear or other failure. Therefore, there exists a need in the art to develop additional treatment regimens, particularly non-invasive or minimally invasive localized techniques, which may be used to reduce the severity of an aneurysm.